1. Field of the Invention
The present invention relates to a process for terminal sterilization of pre-filled plastic and glass syringes and cartridges containing liquid pharmaceutical, biological or veterinary products. More particularly, the invention relates to a process for terminal sterilization of liquid contrast media for parenteral administration contained in plastic and glass syringes and cartridges.
2. Reported Developments
The prior art discloses containers, apparatus and processes for steam-sterilization of products and medical devices used in the health and medical fields where sterility is an absolute requirement. Generally speaking, such sterilization may be accomplished by steam-sterilizing the containers/packages and contents separately, followed by placing the contents into the containers/packages and hermetically sealing the same for use at a later time. Such processes, however, carry the risk of contamination and introduction of pyrogens during the transfer of the products into their containers/packages. The trend in the pharmaceutical industry is toward terminal steam-sterilization wherein the contents are sterilized within their containers/packages.
In the process of steam-sterilization, the pre-filled containers/packages are placed in an autoclave and are subjected to operational cycles which include: purging air from the autoclave chamber by forcing saturated steam therethrough at about a pressure of 1 to 20 psig at a temperature of about 100.degree. C. to 150.degree. C. for about a minute to 30 minutes; further introducing steam into the autoclave chamber so that the temperature of about 100.degree. C. to 125.degree. C. is reached therein; maintaining the temperature for a time sufficient to sterilize the content of the autoclave; cooling the autoclave and removing the containers/packages therefrom. Typical containers containing parenteral formulations, such as glass ampules, stoppered vials and bottles are able to withstand the pressure differentials between the containers and the autoclave chamber created by the operational cycles of the sterilization process. However, pre-filled syringes and cartridges made of plastic or glass do not tolerate significant pressure differential when the internal pressure is greater than the external; such pressure differential results in an unacceptable number of container/package failures that will occur either during the heating phase or the cooling phase of the autoclave cycle.
In the case of glass syringes and cartridges such failure typically will be in the form of plunger blow-out during the heating phase caused by the sum total of product vapor pressure, thermal expansion of the product and the pressure increase of the gas occupying the head space in the container. Should seal integrity be maintained through the heating phase, failure may occur during the cool-down phase of the sterilization cycle when the liquid content in the containers is at or above its boiling point, creating pressures within the containers greater than one atmosphere while the pressure in the autoclave drops to one atmosphere.
In the case of plastic syringes and cartridges, in addition to container/package failure by plunger blow-out during sterilization, the heat and pressure in the autoclave chamber soften the plastic and tend to warp and deform the walls of the containers.
The need to compensate for the elevated internal pressure of a plastic syringe during sterilization was recognized in U.S. Pat. No. 4,718,463 which proposes to maintain a pressure in the autoclave chamber at least equal to the pressure inside the syringe.
We have surprisingly found that pre-filled plastic syringes and cartridges may be steam-sterilized by autoclaving without encountering the above-mentioned problems and without the necessity of maintaining the autoclave pressure at or above the internal pressure of the syringes and cartridges and preferably no head space, in the syringes and cartridges; and providing at least 10% empty space between the plunger and the proximal end of the barrel to allow for sliding movement of the plunger toward the proximal end of the barrel in response to internal pressure generated during the autoclaving cycles.
Pre-filled glass syringes and cartridges having the above-described provisions relating to plastic syringes and cartridges may also be steam-sterilized using an autoclave pressure that is less than the internal pressure of the glass syringes and cartridges. However, we have found that they may also be sterilized using overpressure without the danger of plunger blow-out if the head space is minimized and sufficient plunger movement is allowed in the barrel.